The present invention relates to a therapeutic preparation for anxiety neurosis or depression which comprises a MC4 receptor antagonist as an effective ingredient, and relates to novel piperazine derivatives having a MC4 receptor antagonistic action.
It is suggested by the recent progress of pathophysiology that stress is deeply pertinent to development mechanism of anxiety neurosis and depression. As an intracerebral reaction caused by stress, there has been known a functional abnormality of neuroendocrine system of which representative is the functional abnormality of hypothalamus-pituitary-adrenal system. From such a background, the neuropeptides which locate in pituitary and affect neuroendocrine attract attention as a development reason of depression/anxiety.
Among such neuropeptides are corticotropin releasing factors (CRF) and proopiomelanocortin (POMC). CRF is known to play the central role of stress reaction such as susceptibility of hypothalamus-pituitary-adrenal system, and suggested to have relation to anxiety/depression. Melanocortins [adrenocorticotropic hormone (ACTH), melanocyte stimulating hormone (MSH)] produced from POMC are main neuropeptides in hypothalamus, but there is no report of the substances acting to melanocortin receptors relating to stress reaction and depression/anxiety neurosis.
Melanocortin receptors are classified into 5 subtypes of MC1-MC5. Among these subtypes, melanocortin receptor subtype MC4 is reported as peptidergic selective agonist or antagonist, but there is no report on stress reaction and anti-anxiety action of these agonists or antagonists. Compound 4 of the present invention in Table 1 acts as a high selective antagonist in recombinant human melanocortin receptors.
The relation of melanocortin receptor subtypes and anxiety/depression and stress reaction, and novel piperazine derivatives have been investigated.